Mechanism of progression from bronchioloalveolar carcinoma to invasive adenocarcinoma

细支气管肺泡癌进展为浸润性腺癌的机制

• 批准号: 21590995
• 负责人: TAKIGAWA Nagio
• 金额: $ 2.91万
• 依托单位: Kawasaki Medical School (2011)Okayama University (2009-2010)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590995/
• 关键词: 肺癌; 発癌; EGFR; 肺腺癌; 遺伝子変異

Bronchioloalveolar carcinoma(BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors<1 cm, 1-2 cm, and≧2 cm in diameter, respectively, were analyzed. Of the 24 tumors≦2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component by immunohistochemistry, while pSTAT3 expression was reversed. In the tumors≦2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors. pSTAT3 was identified in the BAC component of 88% of the EGFR mutant(n=17) and 82% of the wild-type tumors(n=33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines(PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor(JSI-124). In conclusion, adenocarcinomas with a BAC component overexpressed pSTAT3 at the margin compared to the center of the tumor. Moreover, STAT3 inhibitors may have therapeutic potential in the inhibition of adenocarcinoma.

细支气管肺泡癌（BAC）型常出现在浸润性腺癌的边缘。我们研究了EGFR信号异常参与腺癌的进展。50例肿瘤来自接受肺腺癌手术的患者，在计算机断层扫描上显示为磨玻璃样阴影的致密区域。分别分析了6例、18例和26例直径<1 cm、1-2 cm和> 2 cm的肿瘤。24个直径> 2cm的肿瘤中，9个为浸润前肿瘤，15个为浸润性肿瘤。EGFR、pAKT和pMAPK在腺癌的中心过表达，而pSTAT 3的表达被逆转。在直径≤ 2cm的肿瘤中，pSTAT 3在浸润前肿瘤中心区的表达高于浸润性肿瘤。在88%的EGFR突变体（n=17）和82%的野生型肿瘤（n=33）的BAC组分中鉴定出pSTAT 3。还研究了表达delE 748-A752 EGFR的转基因小鼠和两种肺癌细胞系（PC-9突变体和A549野生型EGFR）。在转基因小鼠中，pSTAT 3在腺癌中心周围的BAC组分中过表达。过表达pSTAT 3的两种肺癌细胞系对JAK 2/STAT 3抑制剂（JSI-124）同样敏感。总之，与肿瘤中心相比，具有BAC组分的腺癌在边缘处过表达pSTAT 3。此外，STAT 3抑制剂在抑制腺癌方面可能具有治疗潜力。

项目成果

JAK2/STAT3 induces erlotinib-resistance in lung cancer cells harboring EGFR-activating mutations

JAK2/STAT3 诱导携带 EGFR 激活突变的肺癌细胞对厄洛替尼产生耐药性

• 发表时间: 2011
• 作者: Harada Daijiro;Takigawa Nagio;Ohashi Kadoaki;Ichihara Eiki;Kubo Toshio;Takeda Hiromasa;Kashihara Hiromi;Hotta Katsuyuki;Tanimoto Mitsune;Kiura Katsuyuki
• 通讯作者: Kiura Katsuyuki

STAT3 expression in activating EGFR-driven adenocarcinoma of the lung

STAT3 表达激活 EGFR 驱动的肺腺癌

• DOI: 10.1016/j.lungcan.2011.05.015
• 发表时间: 2012
• 期刊: Lung Cancer
• 影响因子: 5.3
• 作者: Takata Saburo;Takigawa Nagio;Segawa Yoshihiko;Kubo Toshio;Ohashi Kadoaki;Kozuki Toshiyuki;Teramoto Norihiro;Yamashita Motohiro;Toyooka Shinichi;Tanimoto Mitsune;Kiura Katsuyuki
• 通讯作者: Kiura Katsuyuki

エクソン19欠失EGFR遺伝子変異陽性肺癌モデルに対するアファチニブの効果

阿法替尼对19号外显子缺失EGFR基因突变阳性肺癌模型的影响

• 发表时间: 2011
• 作者: 二宮崇;瀧川奈義夫;村上斗司;本多宣裕;南大輔;越智宣昭;八杉昌幸;久保寿夫;市原英基;谷本光音;木浦勝行
• 通讯作者: 木浦勝行

Effects of Vandetanib on Lung Adenocarcinoma Cells Harboring Epidermal Growth Factor Receptor T790M Mutation In vivo

• DOI: 10.1158/0008-5472.can-08-4204
• 发表时间: 2009-06-15
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Ichihara, Eiki;Ohashi, Kadoaki;Kiura, Katsuyuki
• 通讯作者: Kiura, Katsuyuki

ERK reactivation mediated by SRC in acquired resistance to gefitinib in non-small cell lung cancer with EGFR mutation

EGFR 突变非小细胞肺癌吉非替尼获得性耐药中 SRC 介导的 ERK 重新激活

• 发表时间: 2011
• 作者: Ochi Nobuaki;Takigawa Nagio;Yasugi Masayuki;Ichihara Eiki;Hisamoto Akiko;Hotta Katsuyuki;Tabata Masahiro;Tanimoto Mitsune;Kiura Katsuyuki
• 通讯作者: Kiura Katsuyuki